Multiple Mieloma

malignancy of plasma cells Characterized :

replacement of the bone marrow by plasma cells (B cell) bone destruction paraprotein formation (monoclonal Gammopathy / spike M immunoglobulin).

How Plasma Cells Work

Develop

from stem cells in bone marrow Stem cells develop into B cells (B lymphocytes) Antigens enter body then B cells develop into plasma cells Produce antibodies

Diagnostic Criteria
Major criteria I. Plasmacytoma on tissue biopsy II. Bone marrow plasma cell > 30% III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl, IgA > 2g/dl, light chain > 1g/dl in 24h urine sample Minor criteria a. Bone marrow plasma cells 10-30% b. M spike but less than above c. Lytic bone lesions d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

Diagnostic Criteria for Multiple Myeloma

Diagnosis:

I + b, I + c, I + d II + b, II + c, II + d III + a, III + c, I II + d a + b + c, a +b + d

Patophisiology

Replacement of the bone marrow leads initially to anemia and later to general bone marrow failure. Malignant plasma cells can form tumors (plasmacytomas) that may cause spinal cord compression. Bone involvement causes bone pain, osteoporosis, lytic lesions, pathologic fractures, and hypercalcemia. The activation of osteoclast in myeloma Very high paraprotein levels (either IgG or IgA) may cause hyperviscosity. The light chain component of the immunoglobulin often leads to renal failure (often aggravated by hypercalcemia). Light chain components may be deposited in tissues as amyloid

Differential Diagnosis

a monoclonal paraprotein, the distinction between myeloma and monoclonal gammopathy of unknown significance (MGUS) must be made.

MGUS is present in 1% of all adults and 3% of adults over age 70 years. MGUS is far more common than myeloma. MGUS will have a monoclonal IgG spike less than 2.5 g/dL, and the height of the spike remains stable MGUS progresses to overt malignant disease, but this may take many years.

Myeloma is distinguished from MGUS by findings of replacement of the bone marrow, bone destruction, and progression. Myeloma must be distinguished from reactive polyclonal hypergammaglobulinemia.

Waldenstrom's macroglobulinemia, lymphomas, and primary amyloidosis (with which it is commonly associated).

Definite Therapy

Most commonly, patients require treatment at diagnosis because of bone pain or other symptoms related to the disease. Chemotherapy:

The combination of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) melphalan as primary treatment in younger patients because of the lack of bone marrow and stem cell damage. The combination of thalidomide plus dexamethasone is as effective as VAD chemotherapy for initial disease control, and is being increasingly used.

The optimal initial therapy for patients under age 70 years with myeloma is autologous stem cell transplantation. Allogeneic transplantation is potentially curative in myeloma, but its role has been limited because of the unusually high mortality rate (40-50%) in myeloma patients.

Supportif Therapy

Localized radiotherapy may be useful for palliation of bone pain or for eradicating tumor at the site of pathologic fracture. Hypercalcemia should be treated aggressively and immobilization and dehydration avoided. The bisphosphonates (pamidronate 90 mg or zoledronate 4 mg intravenously monthly) reduce pathologic fractures in patients with significant bony disease and are an important adjunct in this subset of patients.

Prognosis

The median survival of patients with myeloma has been 3 years The prognosis is affected by : high paraprotein spikes, renal failure, hypercalcemia, or extensive bony disease. (stage I) if the IgG spike is less than 5 g/dL, there is no more than one lytic bone lesion, and there is no evidence of hypercalcemia or renal failure. A median survival of 5-6 years. (stage III) have an IgG spike greater than 7 g/dL, hematocrit less than 25%, calcium greater than 12 mg/dL, or more than three lytic bone lesions. A median survival of 1-2 years Broader use of immunotherapy with allogeneic transplantation may improve the outlook further

POLYCYTHEMIA VERA
Essentials of Diagnosis
Increased red blood cell mass. Splenomegaly. Normal arterial oxygen saturation. Usually elevated white blood count and platelet count.

Causes of polycythemia

Spurious polycythemia Secondary polycythemia Hypoxia: cardiac disease, pulmonary disease, high altitude Carboxyhemoglobin: smoking Renal lesions Erythropoietin-secreting tumors (rare) Abnormal hemoglobins (rare) Polycythemia vera

General Considerations

acquired myeloproliferative disorder overproduction of all three hematopoietic cell lines, most prominently the red blood cells. The hematocrit is elevated (at sea level) when values exceed 54% in males or 51% in females (Table 13-15). Must determine whether true polycythemia or relative polycythemia exists. Normal values for red blood cell mass are 26-34 mL/kg in men and 21-29 mL/kg in women.

Relative ("spurious") polycythemia presents in middleaged men who are overweight and hypertensive (often on diuretic therapy); the hematocrit is almost always less than 60%, and they have a high-normal red cell mass and a low-normal plasma volume. If the red blood cell mass is increased, it is necessary to determine whether the increase is primary or secondary. Primary polycythemia (polycythemia vera) is a bone marrow disorder characterized by autonomous overproduction of erythroid cells. Erythroid production is independent of erythropoietin, and the serum erythropoietin level is low. In vitro, erythroid progenitor cells grow without added erythropoietin, a finding not seen in normal individuals.

Symptoms and Signs

Symptoms related to expanded blood volume and increased blood viscosity. Common complaints include headache, dizziness, tinnitus, blurred vision, and fatigue. Generalized pruritus, especially following a warm shower or bath, may be a striking symptom and is related to histamine release Epistaxis. This is probably related to engorgement of mucosal blood vessels in combination with abnormal hemostasis due to qualitative abnormalities in platelet function. Sixty percent of patients are men, and the median age at presentation is 60 years. Polycythemia rarely occurs in persons under age 40 years.

Physical examination

Plethora and engorged retinal veins. Sleen is palpable in 75% of cases but is nearly always enlarged when imaged. Thrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death in this disorder. Thrombosis appears to be related to increased blood viscosity and abnormal platelet function. Uncontrolled polycythemia leads to a very high incidence of thrombotic. Paradoxically, in addition to thrombosis, increased bleeding also occurs. (peptic ulcer disease).

Laboratory Findings

The hallmark of polycythemia vera is a hematocrit above normal, at times greater than 60%. Red blood cell morphology is normal. Red blood cell mass is elevated. White blood count is elevated to 10,000-20,000/uL platelet count is variably increased, sometimes to counts exceeding 1,000,000/uL. Platelet morphology is usually normal. White blood cells are usually normal, but basophilia and eosinophilia are frequently present. The bone marrow is hypercellular, with panhyperplasia of all hematopoietic elements. Iron stores are usually absent from the bone marrow Vitamin B12 levels are strikingly elevated because of increased levels of transcobalamin III (secreted by white blood cells). Overproduction of uric acid may lead to hyperuricemia.

Differential Diagnosis

Spurious polycythemia, in which an elevated hematocrit is due to contracted plasma volume rather than increased red cell mass A secondary cause of polycythemia should be suspected if splenomegaly is absent and the high hematocrit is not accompanied by increases in other cell lines. Arterial oxygen saturation should be measured to determine if hypoxia is the cause. A smoking history should be taken; carboxyhemoglobin levels may be elevated in smokers. A renal CT scan or sonogram may be considered to look for an erythropoietin-secreting cyst or Polycythemia vera should be differentiated from other myeloproliferative disorders (ET, CML)

Treatment

Phlebotomy. One unit of blood (approximately 500 mL) is removed weekly until the hematocrit is less than 45%; the hematocrit is maintained at less than 45% by repeated phlebotomy as necessary. myelosuppressive therapy is indicated. Indications include a high phlebotomy requirement, thrombocytosis, and intractable pruritus. Alkylating agents have been shown to increase the risk to acute leukemia Hydroxyurea is now being widely used when myelosuppressive therapy is indicated Anagrelide is used in treatment of thrombocytosis and may prove valuable. Low-dose aspirin (81-325 mg daily) has been shown to reduce the risk of thrombosis without excessive bleeding Allopurinol may be indicated for hyperuricemia. Antihistamine may be helpful for control of pruritus,.

Prognosis

Polycythemia is an indolent disease with median survival of 11-15 years. The major cause of morbidity and mortality is arterial thrombosis. Polycythemia vera may convert to myelofibrosis or to chronic myelogenous leukemia. In approximately 5% of cases, the disorder progresses to acute myelogenous leukemia, which is usually refractory to therapy.